Panic Disorder Research Paper

The terms ‘PD’ and ‘panic attack’ first appeared in the diagnostic nomenclature with the publication of the third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III, American Psychiatric Association 1980). Initially, panic attacks were seen primarily as a feature of agoraphobia. In DSM-III, agoraphobia could be diagnosed with or without panic attacks, and individuals who experienced unexpected panic attacks in the absence of agoraphobia received a diagnosis of PD without agoraphobia.

More recently (e.g., DSM-IV, American Psychiatric Association 1994), the relationship between panic disorder and agoraphobia has reversed, such that PD is seen as the primary problem, and agoraphobia is viewed as a complication of PD. The disorder ‘agoraphobia with panic attacks’ has essentially been replaced with ‘panic disorder with agoraphobia’ to reflect the fact that, in clinical groups, agoraphobia tends to develop as a response to having unexpected panic attacks, rather than the other way around (Craske and Barlow 1988).

1. Definitions And Description

1.1 Panic Attack

DSM-IV (American Psychiatric Association 1994) defines a panic attack as a period of intense fear of discomfort that begins quickly and peaks in ten minutes or less. A panic attack must also be accompanied by at least four out of a list of 13 symptoms, which includes eleven physical sensations (i.e., racing or pounding heart, sweating, trembling, shortness of breath, choking feelings, chest discomfort, nausea, dizziness, feelings of unreality or depersonalization, numbness or tingling sensations, hot flashes or chills) and two cognitive symptoms (i.e., fear of losing control or going crazy, fear of dying).

Panic attacks are common in the general population and are also associated with a broad range of psychological problems. For example, people who experience intense worry may have a panic attack in response to a particular worrisome thought. Individuals who are fearful of a specific situation (e.g., seeing a spider, being in a high place) may experience panic attacks when confronted with these situations. Panic attacks may also occur in the absence of any obvious cue or trigger. In fact, the hallmark symptom of PD is the presence of panic attacks that occur out of the blue.

1.2 Panic Disorder

People who suffer from PD experience recurrent unexpected or uncued panic attacks. In addition, they must experience, for at least one month, one or more of the following: (a) persistent worry about having more panic attacks; (b) frequent worry about the implications of consequences of the attacks (e.g., that an attack will lead to a heart attack, death, fainting, diarrhea, vomiting, embarrassment, or some other catastrophe); or (c) a significant change in behavior related to the attacks (e.g., avoidance of certain situations or activities). Finally, before assigning a diagnosis of PD, the clinician must establish that the panic attacks are not directly related to another psychological problem (e.g., a specific phobia), a medical condition (e.g., hyperthyroidism), or use of a substance (e.g., cocaine, caffeine). Panic disorder may be diagnosed with or without agoraphobia.

1.3 Agoraphobia

A significant proportion of individuals suffering from PD develop agoraphobia, a fear of situations in which escape might be difficult, or in which help might not be available in the event of a panic attack (American Psychiatric Association 1994). Typical situations that are often avoided by people with agoraphobia include crowded places (e.g., concerts, movies, shopping malls), driving, traveling, public transportation, flying, enclosed places, and meetings. For some individuals with agoraphobia, it is the distance from home, rather than the situation itself, that determines the level of fear and avoidance. For example, driving may be difficult, but only if the car ventures more than a few kilometers from home. For many people who suffer from agoraphobia, entering feared situations is easier if accompanied by a safe person, such as a spouse, family member, or close friend. In extreme cases, agoraphobia may be associated with a complete inability to leave the home, even when accompanied.

In addition to the obvious avoidance associated with agoraphobia, individuals with PD often engage in more subtle forms of avoidance. For example, a person might see a movie in a theater, but only if sitting in an aisle seat, near the exit. Or an individual might agree to ride a bus only while engaging in distracting behaviors such as reading or listening to a portable radio. Individuals with PD may also carry objects with them to feel safer, including medication, extra money in case of an emergency, or a portable telephone. Finally, they may engage in overprotective behaviors such as frequently checking their heart rate or blood pressure.

2. Epidemiology, Onset, And Demographics

Antony and Swinson (2000) reviewed the literature concerning age of onset and risk factors for developing PD. PD begins on average when a person is in his or her mid-to late-20s, although onset can occur any time between childhood and late in life. Risk factors include a period of life stress preceding the first attack, being female, a history of childhood separation anxiety, and a history of either substance abuse or dependence (Antony and Swinson 2000).

In the National Comorbidity Survey (a study of over 8,000 Americans in the general population), 3.5 percent of individuals reported symptoms meeting criteria for panic disorder with or without agoraphobia at some time in their life (Kessler et al. 1994). The lifetime prevalence of agoraphobia was 6.7 percent, with about two-thirds of agoraphobics having no prior history of panic attacks or panic disorder (Magee et al. 1996). This finding is in direct contrast to studies based on individuals in clinical settings, where agoraphobia almost never occurs separately from panic disorder (Pollard et al. 1989).

People with PD report impairment across a broad range of life domains including work, recreation, and social functioning (Antony et al. 1998). Furthermore, PD is associated with enormous costs to sufferers and to society, in the form of increased heath-care utilization, lost wages, and time off work (e.g., Greenberg et al. 1999). PD is also associated with a higher risk of developing other psychological problems, including other anxiety disorders, depression, certain personality disorders (e.g., dependent, avoidant), and substance-use disorders (for a review, see Antony and Swinson 2000).

3. Biological Approaches To Understanding Panic Disorder

3.1 Biological Models Of Panic Disorder

Most biological approaches to understanding PD have assumed a dysfunction in one or more neurotransmitter systems, including norepinephrine (NE), serotonin (5-HT), and cholecystokinin (CCK). In addition, theorists have hypothesized that genetic and neuroanatomical factors are also involved in the development of PD.

Perhaps the most influential biological model of PD in recent years has been Donald Klein’s suffocation alarm model (Klein 1993), which proposes that panic attacks are caused by a pathological misfiring of the suffocation alarm system. According to Klein, humans are equipped with two types of alarm reactions. The first is controlled by the hypothalamic–pituitary– adrenal (HPA) axis and is responsible for dealing with real or perceived emergency situations. It is this alarm system that is activated when an individual is confronted with a feared object or situation.

The second alarm system is the suffocation alarm system, which is mediated by an area of the brain known as the locus ceruleus. This alarm system is triggered by increased levels of carbon dioxide in the blood, a sign that individuals might be in a small enclosed area, forced to breathe their own exhaled air, which is rich in carbon dioxide. Klein hypothesized that unexpected panic attacks occur when an individual has a pathologically lowered threshold for the activation of the suffocation alarm system. Presumably, the brains of such individuals are prone to mistakenly conclude that there is not enough air to breathe. As reviewed elsewhere (Antony and Swinson 2000), evidence regarding Klein’s model has been mixed.

3.2 Evidence Regarding Biological Approaches To Panic

Despite inconsistent evidence for Klein’s model, there are many studies supporting the view that biological processes are involved in the pathophysiology of PD. PD tends to run in families and evidence from twin studies suggests that genetics plays a significant role in the transmission of PD across generations (e.g., Kendler et al. 1992). Findings from brain-imaging studies suggest that the temporal areas of the brain (particularly the right hippocampal region) are involved in the experience of panic attacks and fear (for a review, see Antony and Swinson 2000).

Evidence regarding the role of neurotransmitters in PD have included studies of altered receptor functioning, levels of particular neurotransmitters and related metabolites, and responses to substances that are known to cause changes in neurotransmitter levels. Among neurotransmitters, NE is the one most often implicated in PD and agoraphobia (Sullivan et al. 1999), although other neurotransmitter systems, such as 5-HT (Bell and Nutt 1998) and CCK (Bradwejn 1995) may also play a role. There is evidence that levels of NE metabolites predict panic-related symptoms (Garvey et al. 1990) and of altered NE receptor sensitivity in people suffering from PD (Nutt 1989). In addition, drugs that block the reuptake of NE appear to be effective for preventing panic attacks (Mavissakalian and Perel 1989).

Finally, a large number of studies have shown that certain substances that affect the NE system are more likely to trigger panic attacks in people with PD than in various comparison groups. Infusions of sodium lactate, carbon-dioxide inhalation, and yohimbine injections have all been shown to trigger panic attacks. However, it should be noted that psychological factors such as perceived control over the procedure and the presence of a safe person can influence whether an individual will experience a panic attack following exposure to these substances (for a review of panic induction studies, see Antony and Swinson 2000).

4. Psychological Approaches To Understanding Panic Disorder

4.1 Psychological Models Of Panic Disorder

Attempts to explain PD using a psychological framework have come from a broad range of theoretical perspectives, including cognitive theory, learning theory, and psychodynamic theory. However, the most influential of these models have been those developed by cognitive and behavioral theorists such as David M. Clark (Clark 1986) and David H. Barlow (Barlow 1988).

From a cognitive behavioral perspective, PD is viewed as being maintained by a fear of benign physical sensations. For example, according to David Clark’s cognitive model of PD, panic attacks stem from a tendency to misinterpret normal physical sensations (e.g., racing heart, dizziness) as indicating some immediate danger. As a result of interpreting these sensations as being threatening, the symptoms escalate, leading to further catastrophic interpretations and predictions. Very quickly, the symptoms spiral into a full-blown panic attack, seemingly out of the blue. Clark and other cognitive theorists acknowledge that biological factors may also contribute to the experience of panic. The sensations that initially start the panic cycle may be caused by caffeine, intense emotions, exercise, hormonal changes, fatigue, hunger, hyperventilation, attention to bodily feelings, or other factors. Consistent with the cognitive behavioral view, 70 percent of individuals with PD report that their panic attacks are triggered by a physical sensation (Breitholtz et al. 1998).

4.2 Evidence Regarding Psychological Approaches To Panic

A number of studies have confirmed that people with PD are fearful of the physical sensations associated with panic attacks, compared to people without PD and people with other anxiety disorders (e.g., Taylor et al. 1992). In addition, researchers have demonstrated that people with PD are more likely than others to interpret ambiguous physical sensations as a sign of some impending physical or mental disaster and to believe these thoughts quite strongly (Clark et al. 1997).

Numerous studies have also found that people with PD have information-processing biases that are consistent with their fears. For example, a number of studies have found that PD is associated with a heightened ability mentally to track physical sensations such as heart rate (e.g., van der Does et al. 2000). In addition, results from studies of attention and memory have also been consistent with psychological models of PD. Compared to people without PD, individuals with PD attend more to threat-related information (e.g., McNally et al. 1994) and are more likely than nonanxious individuals to show threat- related biases in memory (e.g., Amir et al. 1996).

In summary, individuals with PD are typically more fearful of and more vigilant for panic-related sensations, compared to people without PD. PD is also associated with a tendency to hold fearful beliefs about panic-related sensations, and to show biases in attention and memory for threat-related information.

5. Treatment Of Panic Disorder

In 1998, the American Psychiatric Association published practice guidelines for the treatment of PD. In addition to discussing important issues in the assessment and treatment of this condition, the guidelines reviewed the main approaches that have been shown to be useful for treating PD. Essentially, these approaches include treatment with medications, and treatment with cognitive-behavior therapy (CBT). A review of studies on the relative and combined effects of these interventions is available elsewhere (e.g., Antony and Swinson 2000). A brief summary of the major findings is provided below.

5.1 Medication Treatments

A large number of controlled clinical trials have established that certain medications are useful for treating PD with and without agoraphobia. The tricyclic antidepressant imipramine is the most extensively studied medication that has been shown to be effective for blocking panic attacks (e.g., Mavissakalian and Perel 1989). More recently, controlled trials have established that the selective serotonin reuptake inhibitors or SSRIs (e.g., fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram) are also useful for treating PD; in fact, the SSRIs are now often considered to be the pharmacological treatment of choice for this condition (for a review, see Antony and Swinson 2000).

Finally, controlled trials have found a number of other antidepressants to be useful, including venlafaxine (a new antidepressant) (Pollack et al. 1996) and phenelzine (a monoamine oxidase inhibitor or MAOI) (Buigues and Vallejo 1987). Studies with high-potency benzodiazepine anxiolytics such as alprazolam have consistently shown these medications to be effective as well (e.g., Ballenger et al. 1988).

Despite the long list of medication options for treating PD, there is little consistent evidence that any one of these medications is more effective than the others. Choosing among medications for a particular individual usually depends on factors such as potential side effects, possible problems during discontinuation (e.g., rebound anxiety), the patient’s previous history of treatment response, the cost of the drug, and potential interactions with other medications, substances, or medical illnesses.

5.2 Cognitive-Behavior Therapy

Cognitive-behavior therapy for PD includes four main types of strategies: (a) exposure to feared situations such as crowds, public transportation, and being away from home alone (i.e., in vivo exposure); (b) exposure to exercises that trigger feared sensations (e.g., over-breathing or spinning to induce feelings of dizziness); (c) cognitive therapy (i.e., systematically considering evidence that contradicts fearful thinking); and (d) relaxation-based strategies (e.g., learning to slow down one’s breathing). Most of the time, treatment includes various combinations of these strategies.

A number of comprehensive reviews on CBT for PD have been published (e.g., Antony and Swinson 2000, Barlow and Brown 1996, McNally 1994). Generally, there is little evidence that it is necessary to include all four treatment components to achieve maximum results. In vivo exposure to feared situations appears to be particularly important for treating individuals who are agoraphobic. In addition, relaxation-based strategies are thought to be less important than the exposure-based and cognitive techniques.

Although CBT for PD lasts 10 to 15 sessions, a number of recent studies suggest that gains can be made relatively quickly, with a minimal investment of therapist time. For example, telephone-administered CBT has been used to treat people who do not have easy access to a therapist (Swinson et al. 1995) and a single session of CBT has been shown to prevent the onset of PD in a significant percentage of individuals who present to hospital emergency rooms with a panic attack (Swinson et al. 1992). Finally, a number of studies have found that brief CBT lasting only five sessions (Clark et al. 1999) and CBT delivered in a self-help format (e.g., Hecker et al. 1996) are both useful for helping people to overcome PD.

5.3 Combination Treatments

Studies comparing medications, CBT, and their combinations have yielded inconsistent results (Antony and Swinson 2000). However, averaging across a large number of studies, it is reasonable to conclude that both medications and CBT are effective for treating PD and there is no clear evidence favoring either antidepressants, high-potency benzodiazepines, CBT, or their combinations for treating panic attacks (e.g., Bakker et al. 1998, van Balkom et al. 1997). However, the combination of antidepressants and in vivo exposure appears to be particularly useful for treating agoraphobic avoidance (van Balkom et al. 1997).

It should be noted that most studies on the treatment of PD have focused primarily on the short-term effects of treatment over a period of only two to three months. Few studies have examined the relative effects of medications and CBT after treatment is discontinued. Exceptions include three studies comparing the relative and combined effectiveness of CBT with either imipramine (Barlow et al. 2000), alprazolam (Marks et al. 1993), or fluvoxamine (Sharp et al. 1996). In all three studies, individuals who received CBT (alone or in combination with medication) were more likely to maintain their gains over the long term than individuals who received only medication or placebo treatment.

Taken together, the literature on treating PD suggests that CBT and pharmacotherapy are both effective treatments in the short term. However, there is evidence that CBT is a more effective treatment for ensuring that gains are maintained over the long term.

Bibliography:

1. American Psychiatric Association 1980 Diagnostic and Statistical Manual of Mental Disorders, 3rd edn. (DSM-III). American Psychiatric Association, Washington, DC
2. American Psychiatric Association 1994 Diagnostic and Statistical Manual of Mental Disorders, 4th edn. (DSM-IV). American Psychiatric Association, Washington, DC
3. American Psychiatric Association 1998 Practice guideline for the treatment of patients with panic disorder. American Journal of Psychiatry 155, suppl.: 1–34
4. Amir N, McNally R J, Riemann B C, Clements C 1996 Implicit memory bias for threat in panic disorder: Application of the ‘white noise’ paradigm. Behaviour Research and Therapy 34: 157–62
5. Antony M M, Roth D, Swinson R P, Huta V, Devins G M 1998 Illness intrusiveness in individuals with panic disorder, obsessive compulsive disorder, or social phobia. Journal of Nervous and Mental Disease 186: 311–15
6. Antony M M, Swinson R P 2000 Phobic Disorders and Panic in Adults: A Guide to Assessment and Treatment. American Psychological Association, Washington, DC
7. Bakker A, van Balkom A J L M, Spinhoven P, Blaauw B M J W, van Dyck R 1998 Follow-up on the treatment of panic disorder with or without agoraphobia: A quantitative review. Journal of Nervous and Mental Disease 186: 414–19
8. Ballenger J C, Burrows G D, DuPont R L, Lesser I M, Noyes R, Pecknold J C, Rifkin A, Swinson R 1988 Alprazolam in panic disorder and agoraphobia: Results from a multicenter trial. Archives of General Psychiatry 45: 413–22
9. Barlow D H 1988 Anxiety and its Disorders: The Nature and Treatment of Anxiety and Panic. Guilford, New York
10. Barlow D H, Brown T A 1996 Psychological treatments for panic disorder and panic disorder with agoraphobia. In: Mavissakalian M R, Prien R F (eds.) Long-term Treatments of Anxiety Disorders. American Psychiatric Press, Washington, DC, pp. 221–40
11. Barlow D H, Gorman J M, Shear M K, Woods S W 2000 A randomized controlled trial of cognitive-behavioral treatment vs. imipramine and their combination for panic disorder: Primary outcome results. JAMA—Journal of the American Medical Association 283: 2529–36
12. Bell C J, Nutt D J 1998 Serotonin and panic. British Journal of Psychiatry 172: 465–71
13. Bradwejn J 1995 Cholecystokinin and panic disorder. In: Bradwejn J, Vasar E (eds.) Cholecystokinin and Anxiety: From Neuron to Behavior. R. G. Landes, Austin, TX, pp. 73–86
14. Breitholtz E, Westling B E, Ost L G 1998 Cognitions in generalized anxiety disorder and panic disorder. Journal of Anxiety Disorders 12: 567–77
15. Buigues J, Vallejo J 1987 Therapeutic response to phenelzine in patients with panic disorder and agoraphobia with panic attacks. Journal of Clinical Psychiatry 48: 55–9
16. Clark D M 1986 A cognitive approach to panic. Behaviour Research and Therapy 24: 461–70
17. Clark D M, Salkovskis P M, Hackmann A, Wells A, Ludgate J, Gelder M 1999 Brief cognitive therapy for panic disorder: A randomized controlled trial. Journal of Consulting and Clinical Psychology 67: 583–89
18. Clark D M, Salkovskis P M, Ost L G, Breitholtz E, Koehler K A, Westling B E, Jeavons A, Gelder M 1997 Misinterpretation of body sensations in panic disorder. Journal of Consulting and Clinical Psychology 65: 203–13
19. Craske M G, Barlow D H 1988 A review of the relationship between panic and avoidance. Clinical Psychology Review 8: 667–85
20. Garvey M, Noyes R, Cook B 1990 Comparison of panic disordered patients with high versus low MHPG. Journal of Affective Disorders 20: 7–12
21. Greenberg P E, Sisitsky T, Kessler R C, Finkelstein S N, Berndt
22. E R, Davidson J R T, Ballenger J C, Fyer A J 1999 The economic burden of anxiety disorders in the 1990s. Journal of Clinical Psychiatry 60: 427–35
23. Hecker J E, Losee M C, Fritzler B K, Fink C M 1996 Self-directed versus therapist-directed cognitive behavioral treatment for panic disorder. Journal of Anxiety Disorders 10: 253–65
24. Kendler K S, Neale M C, Kessler R C, Heath A C, Eaves L J 1992 The genetic epidemiology of phobias in women: The interrelationship of agoraphobia, social phobia, situational phobia, and simple phobia. Archives of General Psychiatry 9: 273–81
25. Kessler R C, McGonagle K A, Zhao S, Nelson C B, Hughes M, Eshleman S, Wittchen, H U, Kendler K 1994 Lifetime and 12month prevalence of DSM-III-R psychiatric disorders in the United States: Results from the National Comorbidity Survey. Archives of General Psychiatry 51: 8–19
26. Klein D F 1993 False suffocation alarms, spontaneous panics, and related conditions: An integrative hypothesis. Archives of General Psychiatry 50: 306–17
27. Magee W J, Eaton W W, Wittchen H U, McGonagle K A, Kessler R C 1996 Agoraphobia, simple phobia, and social phobia in the national comorbidity survey. Archives of General Psychiatry 53: 159–68
28. Marks I M, Swinson R P, Basoglu M, Kuch K, Noshirvani H, O’Sullivan G, Lelliott P T, Kirby M, McNamee G, Sengun S, Wickwire K 1993 Alprazolam and exposure alone and combined in panic disorder with agoraphobia: A controlled study in London and Toronto. British Journal of Psychiatry 162: 776–87
29. Mavissakalian M R, Perel J M 1989 Imipramine dose-response relationship in panic disorder with agoraphobia: Preliminary findings. Archives of General Psychiatry 46: 127–31
30. McNally R J 1994 Panic Disorder: A Critical Analysis. Guilford, New York
31. McNally R J, Amir N, Louro C E, Lukach B M, Riemann B C, Calamari J E 1994 Cognitive processing of ideographic emotional information in panic disorder. Behaviour Research and Therapy 32: 119–22
32. Nutt D J 1989 Altered central α -adrenoceptor sensitivity in panic disorder. Archives of General Psychiatry 46: 165–9
33. Pollack M H, Worthington J J, Otto M W, Maki K M, Smoller J W, Manfro G G, Rudolph R, Rosenbaum J F 1996 Venlafaxine for panic disorder: Results from a double-blind placebo-controlled study. Psychopharmacology Bulletin 32: 667–70
34. Pollard C A, Bronson S S, Kenney M R 1989 Prevalence of agoraphobia without panic in clinical settings. American Journal of Psychiatry 146: 559
35. Sharp D M, Power K G, Simpson R J, Swanson V, Moodie E, Anstee J A, Ashford J J 1996 Fluvoxamine, placebo, and cognitive behaviour therapy used alone and in combination in the treatment of panic disorder and agoraphobia. Journal of Anxiety Disorders 10: 219–42
36. Sullivan G M, Coplan J D, Kent J M, Gorman J M 1999 The Noradrenergic system in pathological anxiety: A focus on panic with relevance to generalized anxiety and phobias. Biological Psychiatry 46: 1205–18
37. Swinson R P, Fergus K D, Cox B J, Wickwire K 1995 Efficacy of telephone-administered behavioral therapy for panic disorder with agoraphobia. Behaviour Research and Therapy 33: 465–9
38. Swinson R P, Soulios C, Cox B J, Kuch K 1992 Brief treatment of emergency room patients with panic attacks. American Journal of Psychiatry 149: 944–6
39. Taylor S, Koch W J, McNally R J 1992 How does anxiety sensitivity vary across the anxiety disorders? Journal of Anxiety Disorders 6: 249–59
40. van Balkom A J L M, Bakker A, Spinhoven P, Blaauw B M J W, Smeenk S, Ruesink B 1997 A meta-analysis of the treatment of panic disorder with or without agoraphobia: A comparison of psychopharmacological, cognitive-behavioral, and combination treatments. Journal of Nervous and Mental Disease 185: 510–16
41. van der Does A J W, Antony M M, Barsky A J, Ehlers A 2000 Heartbeat perception in panic disorder: A re-analysis. Behaviour Research and Therapy 38: 47–62